Axel Wester, 1 Hanna Skärstrand, 1 Alexander Lind, 1 Anita Ramelius, 1 Annelie Carlsson, 1 Elisabeth Cedervall, 2 Björn Jönsson, 3 Sten A. Ivarsson, 1 Helena Elding Larsson, 1 Karin Larsson, 4 Bengt Lindberg, 1 Jan Neiderud, 5 Malin Fex, 1 Carina Törn, 1 and Åke Lernmark 1 An Increased Diagnostic Sensitivity of Truncated GAD65 Autoantibodies in Type 1 Diabetes May Be Related to HLA-DQ8 Diabetes 2017;66:735–740 | DOI: 10.2337/db16-0891 N-terminally truncated (96–585) GAD65 (tGAD65) auto- antibodies may better delineate type 1 diabetes than full-length GAD65 (fGAD65) autoantibodies. We aimed to compare the diagnostic sensitivity and specificity be- tween fGAD65 and tGAD65 autoantibodies for type 1 diabetes in relation to HLA-DQ. Sera from children and adolescents with newly diagnosed type 1 diabetes (n = 654) and healthy control subjects (n = 605) were analyzed in radiobinding assays for fGAD65 (fGADA), tGAD65 (tGADA), and commercial 125 I-GAD65 (RSRGADA) autoantibodies. The diagnostic sensitivity and specificity in the receiver operating characteris- tic curve did not differ between fGADA and tGADA. At the optimal cutoff, the diagnostic sensitivity for fGADA was lower than tGADA at similar diagnostic specificities. In 619 patients, 64% were positive for RSRGADA compared with 68% for fGADA and 74% for tGADA. Using non-DQ2/non-DQ8 patients as ref- erence, the risk of being diagnosed with fGADA and tGADA was increased in patients with DQ2/2 and DQ2/8. Notably, logistic regression analysis sug- gested that DQ8/8 patients had an increased risk to be diagnosed with tGADA (P = 0.003) compared with fGADA (P = 0.09). tGADA had a higher diagnostic sen- sitivity for type 1 diabetes than both fGADA and RSRGADA. As DQ8/8 patients represent 10–11% of patients with newly diagnosed type 1 diabetes <18 years of age, tGADA analysis should prove useful for disease classification. GAD (Mr 65 K) autoantibodies (GADA) are strongly associated with type 1 diabetes (1) and are common at clinical onset (2). GADA may be used to classify the type of diabetes, whether autoimmune or nonautoimmune (3). In our previous study of patients with newly diagnosed type 1 diabetes in 1996–2005 in the region Skåne of Sweden, we reported that 5.4% of the patients with type 1 diabetes were negative for seven different islet autoantibodies (2). It may be of value to measure GADA at a higher diagnostic sensi- tivity and specificity to exclude misclassification (4). Further- more, patients with HLA-DQ8 have an increased risk of being diagnosed with insulin autoantibodies (IAA), insulinoma- associated protein 2 autoantibodies (IA-2A), or both, whereas patients with HLA-DQ2 have an increased risk of being di- agnosed with GADA but a reduced risk of being diagnosed with IA-2A (5). The risk of being diagnosed with Zinc transporter 8 autoantibodies (ZnT8A) was associated with HLA-DQ6.4 (2,6). It may therefore be necessary to include HLA-DQ typing to improve the diagnostic sensitiv- ity and specificity for islet autoantibodies. It was recently reported that autoantibodies against N-terminally truncated GAD65 (96–585) (tGAD65) had a better chance to detect individuals who progressed to type 1 diabetes compared with full-length GAD65 (1–585) (fGAD65) in some (7,8), but not all, studies (9). The pos- sibility that autoantibodies against tGAD65 (tGADA) may improve the diagnostic sensitivity and specificity of islet autoantibodies prompted the current study as there are 1 Department of Clinical Sciences, Lund University Clinical Research Centre, Skåne University Hospital, Malmö, Sweden 2 Department of Pediatrics, Ängelholm Hospital, Ängelholm, Sweden 3 Department of Pediatrics, Ystad Hospital, Ystad, Sweden 4 Department of Pediatrics, Kristianstad Hospital, Kristianstad, Sweden 5 Department of Pediatrics, Helsingborg Hospital, Helsingborg, Sweden Corresponding author: Axel Wester, axel.wester.175@student.lu.se. Received 21 July 2016 and accepted 20 December 2016. This article contains Supplementary Data online at http://diabetes .diabetesjournals.org/lookup/suppl/doi:10.2337/db16-0891/-/DC1. © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license. Diabetes Volume 66, March 2017 735 IMMUNOLOGY AND TRANSPLANTATION